PROJECT SUMMARY/ABSTRACT To inform an effective response to the opioid epidemic, understanding the multilevel factors that influence risk of opioid use disorder (OUD) is critical. In addition, although the efficacy of medication-assisted treatment (MAT) for OUD is proven, long-term retention in treatment has been a challenge. Thus, efforts are needed to identify program implementation factors that can be strengthened to improve OUD treatment outcomes. The K01 Award will provide the candidate the requisite skills and mentored research experience necessary to meet her long-term goal of conducting independent, innovative research on OUD and its treatment that can guide strategic investment to prevent OUD and inform implementation of MAT programs to increase patient adherence. This proposal comprises a 5-year plan that includes mentorship by Wade Berrettini, MD, PhD, Brian Schwartz, MD, MS, H. Lester Kirchner, PhD, MS, Danielle Mowery, PhD, MS, and Alanna Kulchak Rahm, PhD, MS; didactic training activities to meet the candidate's training goals; and conduct of a two-phase research project that will provide the candidate with substantive experience leading epidemiologic research using electronic health record (EHR) data and in implementation science. The proposed research will be conducted at Geisinger, an integrated healthcare system serving a large geographically diverse region of Pennsylvania, leveraging its research assets?including a wealth of health-related EHR data and linked genetic data?and the ability to integrate research into the clinical environment. The aims of the research are twofold. Aim 1 centers on the social determinants that engender vulnerability to OUD, evaluating associations of community contextual factors related to socioeconomic, social, and physical conditions with OUD, and the role individual-level genetic risk factors, healthcare factors, and comorbid medical conditions play in these relations. Aim 1 will utilize EHR and genetic data from Geisinger patients (n = 18,728) coupled with secondary data characterizing community factors to conduct a nested case-control study. Aim 2 seeks to understand program implementation factors that impact patient adherence to MAT for OUD. Aim 2 is a mixed methods study that will involve interviews with key informants (n ? 30) to identify multilevel barriers and facilitators influencing MAT success, followed by a survey of adult patients (n = 500) in Geisinger's MAT clinics to quantify factors influencing MAT adherence from a patient perspective. Completion of this research will fulfill the candidate's short-term goals by providing training in: (1) OUD, its treatment, and substance use disorder research; (2) natural language processing; (3) measurement of contextual factors; (4) statistical analysis including multilevel modeling and mediation analysis; (5) gene-environment interaction research; and (6) implementation science. The proposed research will generate evidence to understand novel, understudied risk factors for OUD, with implications for investment in community-level prevention interventions, and how health systems can improve treatment retention among individuals with OUD.